=health =theory =alzheimer's
What causes Alzheimer's disease?
what's known
Alzheimer's disease (hereafter
"AD") is defined by a cluster of mental symptoms, which are largly
memory-related.
AD is associated with aggregations of amyloid protein
("plaques") in the brain, outside cells. According to some people, the
presence of plaques is part of the definition of AD.
Many people with
the mental symptoms of AD
don't have plaques.
Plaque buildup can be present for a long time
(maybe 20 years) before mental symptoms of AD.
AD is also associated
with
neurofibrillary tangles consisting of aggregates of hyperphosphorylated
tau protein ("tangles") inside cells. These generally occur after plaques
do.
Some people
have both plaques and tangles without having the mental symptoms of AD.
The presence of plaques is correlated with the mental symptoms of AD,
but the additional presence of tangles
doesn't appear to be.
Risk of AD is increased by oxidative
stress, such as exposure to certain types of pollution.
AD risk has a
genetic component. The strongest known correlation is
with the APOE ε4 gene; people with 2 copies of it are ~15x as likely to
develop AD. However, AD does not strictly require any particular genetic
markers.
ApoE can increase clearance rate of amyloid proteins, and
the ApoE4 type seems to do that less than other types.
ApoE4
can act as a
transcription factor.
Amyloid protein aggregation can be caused
by excessive phosphorylation of it.
AD generally involves progressive
degeneration of synapses and aberrant sprouting of axon terminals.
the amyloid hypothesis
The amyloid hypothesis (hereafter "AH") is that the mental symptoms of AD are caused by plaques. The mechanism is unknown. A variation of AH is that symptoms of AD are caused by soluble amyloid oligomers, rather than plaques.
Some people have plaques for many
years without developing the symptoms of Alzheimer's. The AH view is that
those people are resilient to the negative effects of plaques for unknown
reasons.
Some people have the mental symptoms of AD but don't have
plaques. The main AH view used to be that those people have plaques that
don't show up well in PET scans, but that's now known to be wrong. The
current main AH view is that those cases are some unknown different disease
that happens to have similar mental symptoms.
Plaques don't directly
explain the presence of tangles. The main AH view is that amyloid proteins
trigger an unknown signalling dysfunction that leads to development of
tangles, possibly involving amyloid oligomers binding to receptors on
neurons. A competing AH view is that tau protein modification is done to
protect against damage from plaques.
Aducanumab is a drug that clears plaques and reduces levels of amyloid oligomers (and was approved on that basis) but doesn't seem to be an effective treatment for AD. It's also expensive and has serious side effects.
aging
My view of physiological aging is that:
1)
Physiological aging is mainly a result of DNA damage, and of mitigations
(such as telomeres) for cancer risk from DNA damage.
2) The most
important cause of DNA damage is usually compounds covalently bonding to
DNA.
3) The most important cause of (2) is usually oxidation of
compounds to reactive forms due to
oxidative stress.
4) The most important causes of oxidative stress are usually superoxide
from mitochondria and hydrogen peroxide from enzymes, but in some cases
pollution is more important.
"I-compounds" are an important
kind of harmful DNA modification. They're naturally occuring covalent DNA
modifications which increase with age in tissues of laboratory animals in
the absence of exogenous carcinogens. When DNA is broken up and
chromatography is done, I-compounds appear as nucleotides with larger
attachments, with a variety of polarities.
My hypothesis about
Alzheimer's disease starts from the above view. The fact that some groups
are trying to reverse aging by adding some signalling molecules or nutrients
implies that some people have different views, but that's my view of aging.
my hypothesis
My view is that AD is caused by the following causal chain:
1) Oxidative
stress creates reactive compounds.
2) Reactive compounds bind to DNA
as I-compounds. Those I-compounds
are more
likely to modify DNA on open chromatin regions, where DNA isn't
protected by its packing.
3) I-compounds form on a certain
silencer S
in an open chromatin region. (Transcription factor binding sites are more
likely to be in open chromatin regions.)
4) Bound I-compounds on S
prevent repressor binding. This causes overexpression of a certain DNA
region R. ApoE4 might bind on or near S, or to a transcription factor that
binds on or near S.
5) Overexpression of R causes overproduction of
an amyloid kinase, a tau kinase, and other proteins.
6a) Amyloid
kinase overproduction leads to over-phosphorylation of amyloid proteins,
which causes them to aggregate, forming plaques.
6b) Tau kinase
overproduction leads to over-phosphorylation of tau proteins, which causes
them to aggregate, forming tangles.
6c) Overexpression of other
proteins, probably protein kinases and/or cytokines, causes other problems
in neurons.
7) (6c) causes some dysfunction in a fraction of
individual neurons.
8) Dysfunction of a fraction of individual
neurons leads to the mental symptoms of AD.
my reasoning
To me, the mental symptoms of AD
imply some dysfunction inside cells. (This view is based on my understanding
of neurons and biochemistry in a complicated way.) So, I was skeptical that
plaques would cause those symptoms.
Based on my understanding of
neural networks, the selective memory loss symptoms of AD are consistent
with a fraction of individual cells being dysfunctional or dying.
If
amyloid oligomers affects receptors, that would be mediated by some complex
multi-factor regulatory system rather than affecting tau protein
phosphorylation directly and selectively. (Biological systems in Animalia
are never that straightforward.) So, it's more likely that kinases for both
proteins are in the same DNA region than that the connection is mediated by
receptors.
If amyloid and tau protein are phosphorylated too much,
overproduction of enzymes that phosphorylate them (kinases) is an obvious
explanation.
If a DNA region produces protein kinases, then it seems
likely to me that it produces mostly protein kinases and cytokines, because
most other proteins are needed in different quantities.
If
Alzheimer's is caused by normal aging, and physiological aging is mainly
caused by DNA modification, then it's more likely to be related to a region
that's often open chromatin, because mutation rates of open chromatin
regions are
higher. If a DNA region is usually open chromatin, it's more
likely to be a transcription factor binding site.
Overproduction of
something requires fewer dysfunctional cells to cause extracellular problems
than underproduction, so the cause of plaques seemed likely to be
overproduction of something.
DNA modification is more likely to block
binding of a transcription factor than improve it. So, if DNA modification
causes overproduction of proteins in a DNA region, it's probably blocking
silencer binding.
implications
If my hypothesis about AD is
correct, what does that imply about AD treatment and research? It implies
that targeting plaques and amyloid oligomers is probably not an effective
approach for AD treatment, but what would more productive approaches be?
If AD is caused by oxidative stress causing DNA modification, then some
antioxidants should reduce risk of AD. But of course, such nutritional
studies are very difficult to do effectively. Moderate exercise can also
increase antioxidant levels, while large amounts of high-intensity exercise
increases oxidative stress, so you'd also expect correlations with exercise.
But AD was already known to be correlated with oxidative stress, so these
aren't new proposals; what my hypothesis provides is connecting that known
correlation with the symptoms.
If AD is caused by a particular DNA
region coding for some tau and amyloid kinases, then it should be possible
to find those kinases, then locate the DNA region for them. If AD symptoms
are caused by some kinases or cytokines that can be identified from that DNA
region, then it might be possible to treat AD with small molecules that
inhibit those proteins. (Some tau kinases involved in tau
hyperphosphorylation have
already been found.)
If AD is caused overexpression of a
particular DNA region, it might be possible to reduce expression of it with
small molecules that bind to a promotor for that region and prevent it from
binding to DNA. Targeting transcription factors is relatively difficult, but
there has been
some progress.
Overall, my hypothesis does imply AD is harder
to treat than AH does.
why now?
Looking at my email records, I
told some people a simplified version of the above hypothesis back in 2014.
Why am I posting this now?
The proximate cause is some academic
fraud about amyloid protein being revealed, but I should explain the
reasons I didn't post this earlier and how that news relates to those.
1) With some
key data being fake, and the failure of aducanumab to cure AD, maybe people
are more ready for a new hypothesis now.
2) Key data being fake
lowers the standards for contribution being socially acceptable. If you
publish some amateurish thoughts on physics, you're a crackpot and people
think less of you. On the other hand, if you publish some amateurish
thoughts on economics, they're probably not any worse than things published
in the New York Times. Well, even if someone is a crackpot, that's still
better than publishing papers based on completely fake data, right?
3) I wanted to leave open the option of someone more prestigous than myself
taking most of the credit for developing this hypothesis. At this
point, I don't see much reason to do that.
The main response I got from
people involved in AD research, including a professor and a director at a
research institute, was basically, "This is an interesting idea, but what do
you expect me to do with it?"
How is it possible that principal
investigators wouldn't be able to do anything to pursue an alternative
hypothesis? Grants, paper acceptance, and citation counts are all determined
by community consensus. Also, any alternative hypothesis too far from the
standard one risks diverting funding and prestige from the current standard
one, which many researchers will have specialized in and built a career on.
Even a tenured professor trying to do something too new on their own will
generally lead to them not getting grants or publications in good journals.
So, current institutional incentives tend to lead to ossification of
research communities, such that switching to a new core hypothesis often
requires that the existing community die and a new one be made.
disclaimer
I'm not a doctor or a professor of medicine.
I wrote above that:
- I-compounds
are more likely to modify DNA on open chromatin regions, where DNA isn't
protected by its packing.
- Transcription factor binding sites are more
likely to be in open chromatin regions.
Usually, people are taught that sort of thing. In my case, I understood chemistry well enough for that to seem obvious, searched for the standard terms needed to find papers on that topic, and found some papers confirming my view. This is an unusual basis for knowledge, so I may have some insights that most experts don't, but for the same reasons, I might be lacking some community knowledge they have.